In Alzheimer's Disease (AD), cholinergic neurons are injured early in the course of the disease. In a search for an animal model of cholinergic injury, we have discovered a naturally occurring model of cholinergic dystrophy in older Galagos. Visible damage to cholinergic axons is accompanied in these animals by neuritic and senile plaques, amyloid deposits, and abnormal iron storage in peripheral organs and brain. The cholinergic injury is quite selective and most prominent in the cholinergic fibers innervating the gabaergic-somatostatin neurons of the reticular nucleus of thalamus. We propose to investigate this model through the following specific aims: Specific aim 1: Examine the anatomical and biochemical correlates of age-related cholinergic injury in Galagos, focusing on cholinergic neurons and their gabaergic targets in reticular nucleus of thalamus and striatum - We will use specific immunocytochemistry and hybridization histochemistry, cell- filling injections, and ultrastructural survey. Emphasis will be on early alterations in intermediate metabolism, neurotransmitter and neuroreceptor proteins, amyloid and related AD markers, with and preceding injury. Specific aim 2: Determine whether cholinergic dystrophy is related to abnormal iron storage in peripheral organs and central nervous system - a 4-year study of 24 animals will determine whether the 'naturally' occurring pathology can be accelerated by dietary manipulation. Specific aim 3: Discover whether similar cholinergic dystrophy and abnormal iron distribution might occur in humans with AD. Aged subhuman primates are considered an excellent model for some of the changes seen in AD. In our case, Galagos offer a unique model of early cholinergic injury in AD which occurs at 4-6 years of age in this species. Our investigations will focus on the relationship of this injury to gabaergic neurons and abnormal disposition of body iron in these animals, and on the identification of early biochemical changes in cholinergic and gabaergic neurons that may be important clues to cell vulnerability, pathogenesis, and treatment options. These studies are relevant to brain aging, and to AD.